Ulcerative colitis (UC) is a serious inflammatory disease affecting the colon and then most often the descendens and sigmoideum segments of colon. Morbus Crohn is a dangerous inflammatory bowel disease, sometimes affecting primarily colon but most often affecting the terminal small bowel--the ileum. These inflammatory processes are sensitive to GCS therapy, but hitherto effective long term treatment has been hampered by serious adverse GCS effects in the systemic circulation (eg osteoporosis, precipitation of diabetes, blocked HPA-axis etc).
In order to locally treat the mainly affected distal part of colon, the luminal concentration of steroid in colon must be high enough to allow for intraluminal transport despite a competing systemic absorption in the colon ascendens. The ideal profile for colon-specific therapy would be reached by release of a potent GCS with a very high first pass metabolic inactivation in the liver. There should be a continous and complete release of the active GCS during the colon passage. The best therapy has hitherto been attained with budesonide, which has a favourable combination of high topical potency and substantial hepatic first pass inactivation, Can J Gastroenterol 4:407-414, 1990. To reach colon mucosa of the distal segments by local therapy, budesonide has to be encapsulated in a pharmaceutical formulation, which when given orally starts to release budesonide in the terminal ileum. Such a pharmaceutical formulation is disclosed in PCT/SE90/00738. However, with a pharmaceutical formulation of that kind it is difficult to get a complete GCS release during the colonic transit, which at least in periods of active disease is short and quite variable. Thus, a substantial fraction of GCS is often bypassing the patient without being released.
An approach to more specific therapy of colon, has been a chemical targeting based on bacteria-specific cleavage of a GCS prodrug, e g a .beta.-D-glucoside. In EP 123485 and also in J Med Chem 28:51-57, 1985, in Pharmacutical Res 8:445-454, 1991, and in Advanced Drug Delivery Reviews 7:149-199, 1991, such prodrugs have recently been described based on dexamethasone and hydrocortisone. However, these GCS-glycosides will not be colon-specific as stated, because the released glucocorticosteroids have too low first pass inactivation in the liver (Can. J. Gastroenterol. 4:407-414, 1990). In man a substantial fraction of the GCS released can be anticipated to reach the systemic circulation intact and by that provoke adverse reactions. Furthermore, plain delivery of GCS-glycoside will not lead to the right type of continous colonic release. When the glycoside meets glycosidase-containing bacteria in cecum and ascending colon, a rapid intraluminal hydrolysis and GCS absorption will occur. This reduces markedly the possibilities for subsequent local release in colon transversum, descendens, sigmoideum and rectum, which parts are all more prone to colitis than what ascendens is. This poor local spreading of active GCS from glycosdide prodrug has not been discussed earlier.
The most common location of lesions in Morbus Crohn is the ileum. Once the ileum is affected, these patients are very often operated by resection of terminal ileum including the ileo-caecal valve, which is the valve normally blocking colonic bacterial backwash into the ileum. There is a recent piece of information that this fecal contamination into bowel segments not normally exposed to high bacterial counts, contributes to the common retrograde spreading of serious inflammation and recurrence of clinical disease. Often these patients have to be operated by further ileal resection or to widening of ileal lumen. Current GCS treatment of Morbus Crohn of small bowel is based on conventional tablets releasing their steroid content in upper bowel segments. Because these tablets work via the systemic route and high doses have to be given, serious adverse effects are provoked. Recently retarded formulations have been tested for improving direct release to ileal mucosa. However, with the current type of retarded formulations controlled by pH and osmotic forces, it is not possible to reach a concentrated release of active GCS at the front of bacterial invasion of small bowel. The use of steroid glycosides in local treatment of ileal Morbus Crohn has not been discussed earlier.